Ribociclib (1), or 7-cyclopentyl-N,N-dimethyl-2-{[5-(piperazin-1-yl) pyridin-2-yl]amino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide, in the form of a succinate salt, is the active ingredient in KISQALI®, which is indicated, in combination with an aromatase inhibitor, as initial endocrine-based therapy for the treatment of postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, advanced or metastatic breast cancer.

One method of preparing Ribociclib (1) is described in WO 2010/020675 A1, which discloses a family of compounds that are stated to be useful in treatments and therapies for protein kinase-associated disorders. In this method, which is depicted in Scheme 1, Ribociclib (1) is prepared by Buchwald-type coupling of pyrrolopyrimidine (H1) with the heteroaryl amine (I) to form the compound of formula (J), followed by deprotection of the tert-butoxycarbonyl (BOC)-protected piperazine ring. The pyrrolopyrimidine ring of intermediate (H1) is prepared by cyclization of intermediate (E1), formed from the respective displacement of the chloride and bromide substituents on the pyrrolidine ring of (A1) with cyclopentylamine (B) and masked propynal (C). Following hydrolysis of the acetal group of intermediate (E1), the resulting aldehyde (F1) is oxidized to the acid (G1), which then undergoes amidation with dimethylamine to provide the intermediate (H1).

A similar approach is reported in WO 2012/064805 A2, which uses propargyl alcohol rather than propargylaldehyde acetal (D) in formation of the pyrrolopyrimidine ring. Accordingly, subsequent steps to afford intermediate (H1) are altered and include an oxidation/amidation in the presence of manganese (IV) oxide, sodium cyanide and dimethylamine.
Although WO 2012/064805 A2 reports improved yields over WO 2010/020675 A1, and the elimination of chromatographic purification, these improvements necessitate the introduction of other disadvantages, such as the use of sodium cyanide, a highly toxic and hazardous substance requiring specialised transport, handling and disposal practices. Furthermore, the process requires a large excess of the oxidant, manganese (IV) oxide, which is a pigmented oxidant that stains surfaces and is notoriously difficult to remove from reactors and equipment. These factors lead to undue complexity and cost in the manufacture of Ribociclib (1) in a commercial setting.
A second strategy for the preparation of Ribociclib (1) is described in CN106749259 A. In this approach, which is exemplified in Scheme 2, Ribociclib (1) is prepared by displacement of the sulfonyl group of pyrrolopyrimidine (H2) with heteroaryl amine (I) to form the compound of formula (J), followed by deprotection of the tert-butoxycarbonyl (BOC)-protected piperazine ring. Unlike the prior approaches, the pyrrolopyrimidine ring of intermediate (H2) is prepared by an Aldol-type cyclization of intermediate (E2), which is formed from the displacement of the chloride substituent on the pyrrolidine ring of (A2) with cyclopentylamino ester (L). Following amidation of (F2) with dimethyl amine, the methyl sulfide is oxidized to the sulfone to afford intermediate (H2).
However, the use of chromatography for the purification of intermediate (J), and the use of excess amounts of hazardous and reactive reagents such as sodium hydride, meta-chloroperoxybenzoic acid (MCPBA), and lithium hexamethyldisilamide (LiHMDS), make this process impractical for use on a commercial scale.

Owing to the drawbacks of the existing processes, there remains a need for improved processes for the preparation of Ribociclib (1), and the intermediates used in such preparations, that are more amenable to scale-up and use on a commercial scale.